Prevention of Cardiovascular Events
Lunia is indicated to reduce the risk of cardiovascular events (see section 5.1) in patients
with coronary heart disease(CHD) and a history of acute coronary syndrome (ACS), either
previously treated with a statin or not.
Hypercholesterolemia
Lunia is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous
familial and non-familial) hypercholesterolemia or mixed hyperlipidemia where use of a
combination product is appropriate:
• patients not appropriately controlled with a statin alone
• patients already treated with a statin and ezetimibe
Homozygous Familial Hypercholesterolemia (HoFH)
Lunia is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may
also receive adjunctive treatments (e.g. low-density lipoprotein [LDL] apheresis).

Posology
Hypercholesterolemia
The patient should be on an appropriate lipid-lowering diet and should continue on this diet
during treatment with Lunia.
Route of administration is oral. The dosage range of Lunia is 10/10 mg/day through 10/80
mg/day in the evening. All dosages may not be available. The typical dose is 10/20 mg/day
or 10/40 mg/day given as a single dose in the evening. The 10/80-mg dose is only
recommended in patients with severe hypercholesterolemia and at high risk for
cardiovascular complications who have not achieved their treatment goals on lower doses
and when the benefits are expected to outweigh the potential risks (see sections 4.4 and
5.1). The patient's low-density lipoprotein cholesterol (LDL-C) level, coronary heart disease
risk status, and response to current cholesterol-lowering therapy should be considered when
starting therapy or adjusting the dose.
The dose of Lunia should be individualized based on the known efficacy of the
various dose strengths of Lunia (see section 5.1, Table 2) and the response to the current
cholesterol-lowering therapy. Adjustments of dosage, if required, should be made at intervals
of not less than 4 weeks.
Lunia can be administered with or without food. The tablet should not be split.
Patients with Coronary Heart Disease and ACS Event History
In the cardiovascular events risk reduction study (IMPROVE-IT), the starting dose was 10/40
mg once a day in the evening. The 10/80-mg dose is only recommended when the benefits
are expected to outweigh the potential risks.
Homozygous Familial Hypercholesterolemia
The recommended starting dosage for patients with homozygous familial
hypercholesterolemia is Lunia 10/40 mg/day in the evening. The 10/80-mg dose is only
recommended when the benefits are expected to outweigh the potential risks (see above;
sections 4.3 and 4.4). Lunia may be used as an adjunct to other lipid-lowering treatments
(e.g. LDL apheresis) in these patients or if such treatments are unavailable.
In patients taking lomitapide concomitantly with Lunia, the dose of Lunia must not exceed
10/40 mg/day (see sections4.3, 4.4 and 4.5).
Co-administration with other medicines
Dosing of Lunia should occur either ≥ 2 hours before or ≥ 4 hours after administration of a
bile acid sequestrant.
In patients taking amiodarone, amlodipine, verapamil, diltiazem, or products containing
elbasvir or grazoprevir concomitantly with Lunia, the dose of Lunia should not exceed 10/20
mg/day (see sections 4.4 and 4.5).
In patients taking lipid-lowering doses (≥ 1 g/day) of niacin concomitantly with Lunia, the
dose of Lunia should not exceed 10/20 mg/day (see sections 4.4 and 4.5). 

Elderly
No dosage adjustment is required for elderly patients (see section 5.2).
Pediatric population
Initiation of treatment must be performed under review of a specialist.
Adolescents ≥ 10 years (pubertal status: boys Tanner Stage II and above and girls who are
at least one-year post-menarche): The clinical experience in pediatric and adolescent
patients (aged 10-17 years old) is limited. The recommended usual starting dose is 10/10
mg once a day in the evening. The recommended dosing range is 10/10 to a maximum of
10/40 mg/day (see sections 4.4 and 5.2).
Children < 10 years: Lunia is not recommended for use in children below age 10 due to
insufficient data on safety and efficacy (see section 5.2). The experience in pre-pubertal
children is limited.
Hepatic Impairment
No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score
5 to 6). Treatment with Lunia is not recommended in patients with moderate (Child-Pugh
score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction. (see sections 4.4 and 5.2).
Renal Impairment
No modification of dosage should be necessary in patients with-mild renal impairment
(estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2). In patients with chronic kidney
disease and estimated glomerular filtration rate < 60mL/min/1.73 m2, the recommended
dose of Lunia is 10/20 mg once a day in the evening (see sections 4.4, 5.1, and5.2). Higher
doses should be implemented cautiously.
Method of Administration
Lunia is for oral administration. Lunia can be administered as a single dose in the evening.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. Pregnancy and lactation (see section 4.6). Active liver disease or unexplained persistent elevations in serum transaminases. Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or greater) (e.g.itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV proteaseinhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and drugs containing cobicistat) (see sections 4.4 and 4.5). Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5). In patients with HoFH, concomitant administration of lomitapide with doses > 10/40 mg Lunia (see sections 4.2, 4.4 and4.5).

Myopathy/Rhabdomyolysis
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have
been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with
ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known
tobe associated with increased risk of rhabdomyolysis.
Lunia contains simvastatin. Simvastatin, like other inhibitors of HMG-CoA reductase,
occasionally causes myopathy manifested as muscle pain, tenderness or weakness with
creatine kinase (CK) above 10 X the upper limit of normal(ULN). Myopathy sometimes takes
the form of rhabdomyolysis with or without acute renal failure secondary tomyoglobinuria,
and very rare fatalities have occurred. The risk of myopathy is increased by high levels of
HMG-CoA reductase inhibitory activity in plasma (i.e., elevated simvastatin and simvastatin
acid plasma levels), which may be due, in part, to interacting drugs that interfere with
simvastatin metabolism and/or transporter pathways (see section 4.5).
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related for simvastatin. In a clinical trial database in which 41,413 patients were treated with
simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median
follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%,0.08%
and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully
monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with
simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was
approximately 1.0% compared with 0.02% for patients on 20mg/day. Approximately half of
these myopathy cases occurred during the first year of treatment. The incidence of
myopathy during each subsequent year of treatment was approximately 0.1%. (See sections
4.8 and 5.1).
The risk of myopathy is greater in patients on ezetimibe/simvastatin 10/80 mg compared with
other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 10/80-mg
dose of ezetimibe/simvastatin should only be used in patients with severe
hypercholesterolemia and at high risk for cardiovascular complications who have not
achieved their treatment goals on lower doses and when the benefits are expected to
outweigh the potential risks. In patients taking ezetimibe/simvastatin 10/80 mg for whom an
interacting agent is needed, a lower dose of ezetimibe/simvastatin or an alternative statinbased
regimen with less potential for drug-drug interactions should be used (see below
Measures to reduce the risk of myopathy caused by medicinal product interactions and
sections 4.2, 4.3, and 4.5).
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT),
18,144 patients with coronary heart disease and ACS event history were randomized to
receive ezetimibe/simvastatin 10/40 mg daily (n = 9067) or simvastatin 40 mg daily (n =
9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for
ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as
unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN or two consecutive
observations of CK ≥ 5 and < 10 times ULN. The incidence of rhabdomyolysis was 0.1% for
ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as
unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN with evidence of
renal injury, ≥ 5 times ULN and < 10 times ULN on two consecutive occasions with evidence
of renal injury or CK ≥ 10,000 IU/L without evidence of renal injury. (See section4.8). In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to
receive ezetimibe/simvastatin 10/20 mg daily (n = 4650) or placebo (n = 4620) (median
follow-up 4.9 years), the incidence of myopathy was 0.2% for ezetimibe/simvastatin and
0.1% for placebo (see section 4.8).
In a clinical trial in which patients at high risk of cardiovascular disease were treated with
simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was
approximately 0.05% for non-Chinese patients (n = 7367) compared with 0.24% for Chinese
patients (n = 5468). While the only Asian population assessed in this clinical trial was
Chinese, caution should be used when prescribing ezetimibe/simvastatin to Asian patients
and the lowest dose necessary should be employed.
Reduced function of transport proteins
Reduced function of hepatic OATP transport proteins can increase the systemic exposure of
simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function
can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients
who are carriers of the SLCO1B1 c.521T>C genotype.
Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1
protein have an increased systemic exposure of simvastatin acid and increased risk of
myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in
general, without genetic testing. Based on the results of the SEARCH trial, homozygote
Callele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one
year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is
0.3% in patients having the most common genotype (TT) (see section 5.2). Where available,
genotyping for the presence of the C allele should be considered as part of the benefit-risk
assessment prior to prescribing 80 mg simvastatin for individual patients and high doses
avoided in those found to carry the CC genotype. However, absence of this gene upon
genotyping does not exclude that myopathy can still occur.
Creatine Kinase measurement
Creatine Kinase (CK) should not be measured following strenuous exercise or in the
presence of any plausible alternative cause of CK increase as this makes value
interpretation difficult. If CK levels are significantly elevated at baseline (>5 X ULN), levels
should be re-measured within 5 to 7 days later to confirm the results.
Before the treatment
All patients starting therapy with ezetimibe/simvastatin, or whose dose of
ezetimibe/simvastatin is being increased, should be advised of the risk of myopathy and told
to report promptly any unexplained muscle pain, tenderness or weakness.
Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In
order to establish a reference baseline value, a CK level should be measured before starting
treatment in the following situations:
• Elderly (age ≥65 years)
• Female gender
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse. 

   
In such situations, the risk of treatment should be considered in relation to possible benefit,
and clinical monitoring is recommended. If a patient has previously experienced a muscle
disorder on a fibrate or a statin, treatment with any statin-containing product (such as Lunia)
should only be initiated with caution. If CK levels are significantly elevated at baseline (>5 X
ULN), treatment should not be started.
Whilst on treatment
If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with
ezetimibe/simvastatin, their CK levels should be measured. If these levels are found, in the
absence of strenuous exercise, to be significantly elevated (>5 X ULN), treatment should be
stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are
<5 XULN, treatment discontinuation may be considered. If myopathy is suspected for any
other reason, treatment should be discontinued.
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM)
during or after treatment with some statins. IMNM is clinically characterized by persistent
proximal muscle weakness and elevated serum creatinekinase, which persist despite
discontinuation of statin treatment (see section 4.8).
If symptoms resolve and CK levels return to normal, then re-introduction of
ezetimibe/simvastatin or introduction of another statin-containing product may be considered
at the lowest dose and with close monitoring.
A higher rate of myopathy has been observed in patients titrated to the 80 mg dose of
simvastatin (see section 5.1). Periodic CK measurements are recommended as they may be
useful to identify subclinical cases of myopathy. However, there is no assurance that such
monitoring will prevent myopathy.
Therapy with ezetimibe/simvastatin should be temporarily stopped a few days prior to
elective major surgery and when any major medical or surgical condition supervenes.
Measures to reduce the risk of myopathy caused by medicinal product interactions (see also
section 4.5)
The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of
ezetimibe/simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole,
posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease
inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products
containing cobicistat), as well as ciclosporin, danazol, and gemfibrozil. Use of these
medicinal products is contraindicated (see section 4.3).
Due to the simvastatin component of ezetimibe/simvastatin, the risk of myopathy and
rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses
(≥1 g/day) of niacin or by concomitant use of amiodarone, amlodipine, verapamil or diltiazem
with certain doses of ezetimibe/simvastatin (see sections 4.2 and 4.5). The risk of myopathy
including rhabdomyolysis may be increased by concomitant administration of fusidic acid
with ezetimibe/simvastatin. For patients with HoFH, this risk may be increased by
concomitant use of lomitapide with ezetimibe/simvastatin (see section 4.5).
Consequently, regarding CYP3A4 inhibitors, the use of ezetimibe/simvastatin concomitantly
with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g.
nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, 
and medicinal products containing cobicistat is contraindicated (see sections 4.3 and 4.5). If reatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or
greater) is unavoidable, therapy with ezetimibe/simvastatin must be suspended (and use of
an alternative statin considered) during the course of treatment. Moreover, caution should be
exercised when combining ezetimibe/simvastatin with certain other less potent CYP3A4
inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of
grapefruit juice and ezetimibe/simvastatin should be avoided.
Simvastatin must not be co-administered with systemic formulations of fusidic acid or within
7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid
is considered essential, statin treatment should be discontinued throughout the duration of
fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities)
in patients receiving fusidic acid and statins in combination (see section 4.5). The patient
should be advised to seek medical advice immediately if they experience any symptoms of
muscle weakness, pain or tenderness.
Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In
exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the
treatment of severe infections, the need for co-administration of ezetimibe/simvastatin and
fusidic acid should only be considered on a case-by-case basis under close medical
supervision.
The combined use of ezetimibe/simvastatin at doses higher than 10/20 mg daily with lipidlowering
doses (≥ 1 g/day) of niacin should be avoided unless the clinical benefit is likely to
outweigh the increased risk of myopathy (see sections 4.2 and 4.5).
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant
administration of HMG-CoA reductase inhibitors and lipid-modifying doses (≥ 1 g/day) of
niacin (nicotinic acid), either of which can cause myopathy when given alone.
In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular
disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without
ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the
addition of lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid). Therefore, physicians
contemplating combined therapy with simvastatin and lipid-modifying doses (≥ 1 g/day) of
niacin (nicotinicacid) or products containing niacin should carefully weigh the potential
benefits and risks and should carefully monitor patients for any signs and symptoms of
muscle pain, tenderness, or weakness, particularly during the initial months of therapy and
when the dose of either medicinal product is increased.
In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese
patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for
Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg co-administered
with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian
population assessed in this clinical trial was Chinese, because the incidence of myopathy is
higher in Chinese than in non-Chinese patients, co-administration of ezetimibe/simvastatin
with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) is not recommended in Asian
patients.
Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for
muscle related toxic effects may be similar to niacin. The combined use of ezetimibe/simvastatin at doses higher than 10/20 mg daily with
amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH,
the combined use of ezetimibe/simvastatin at doses higher than 10/40 mg daily with
lomitapide must be avoided (see sections 4.2, 4.3 and 4.5).
Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4
at therapeutic doses concomitantly with ezetimibe/simvastatin, particularly higher
ezetimibe/simvastatin doses, may have an increased risk of myopathy. When coadministering
ezetimibe/simvastatin with a moderate inhibitor of CYP3A4 (agents that
increase AUC approximately 2-5-fold), a dose adjustment may be necessary. For certain
moderate CYP3A4 inhibitors, e.g. diltiazem, a maximum dose of 10/20 mg
ezetimibe/simvastatin is recommended (see section 4.2).
Simvastatin is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter.
Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and
grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased
risk of myopathy; therefore, a dose adjustment of simvastatin should be considered
depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with
simvastatin has not been studied; however, the dose of Lunia should not exceed 10/20
mg daily in patients receiving concomitant medication with products containing
elbasvir or grazoprevir (see section 4.5).
The safety and efficacy of ezetimibe/simvastatin administered with fibrates have not been
studied. There is an increased risk of myopathy when simvastatin is used concomitantly with
fibrates (especially gemfibrozil). Therefore, concomitant use of ezetimibe/simvastatin with
gemfibrozil is contraindicated (see section 4.3) and concomitant use with other fibrates is not
recommended (see section 4.5).
Daptomycin
Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase
inhibitors (e.g. simvastatin and ezetimibe/simvastatin) co-administered with daptomycin.
Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin,
as either agent can cause myopathy and/or rhabdomyolysis when given alone.
Consideration should be given to temporarily suspend ezetimibe/simvastatin in patients
taking daptomycin unless the benefits of concomitant administration outweigh the risk.
Consult the prescribing information of daptomycin to obtain further information about this
potential interaction with HMG-CoA reductase inhibitors (e.g. simvastatin and
ezetimibe/simvastatin) and for further guidance related to monitoring. (See section 4.5).
Liver Enzymes
In controlled co-administration trials in patients receiving ezetimibe with simvastatin,
consecutive transaminase elevations (≥ 3 X ULN) have been observed (see section 4.8).
In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were
randomized to receive ezetimibe/simvastatin 10/40 mg daily (n = 9067) or simvastatin 40 mg
daily (n = 9077). During a median follow-up of 6.0 years, the incidence of consecutive
elevations of transaminases (≥ 3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for
simvastatin (see section 4.8).
In a controlled clinical study in which over 9000 patients with chronic kidney disease were
randomized to receive ezetimibe/simvastatin 10/20 mg daily (n = 4650), or placebo (n =
4620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of    
transaminases (> 3 X ULN) was 0.7% for ezetimibe/simvastatin and 0.6% for placebo (see
section 4.8).
It is recommended that liver function tests be performed before treatment with
ezetimibe/simvastatin begins and thereafter when clinically indicated. Patients titrated to the
10/80-mg dose should receive an additional test prior to titration, 3 months after titration to
the 10/80-mg dose, and periodically thereafter (e.g. semiannually) for the first year of
treatment. Special attention should be paid to patients who develop elevated serum
transaminase levels, and in these patients, measurements should be repeated promptly and
then performed more frequently. If the transaminase levels show evidence of progression,
particularly if they rise to 3 X ULN and are persistent, the drug should be discontinued. Note
that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy
(see above Myopathy/Rhabdomyolysis).
There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients
taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment with ezetimibe/simvastatin promptly
interrupt therapy. If an alternate etiology is not found, do not restart ezetimibe/simvastatin.
Ezetimibe/simvastatin should be used with caution in patients who consume substantial
quantities of alcohol.
Hepatic impairment
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate
or severe hepatic impairment, Lunia is not recommended (see section 5.2).
Diabetes mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at
high risk of future diabetes, may produce a level of hyperglycemia where formal diabetes
care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with
statins and therefore should not be a reason for stopping statin treatment. Patients at risk
(fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m2, raised triglycerides, hypertension)
should be monitored both clinically and biochemically according to national guidelines.
Pediatric population
Efficacy and safety of ezetimibe co-administered with simvastatin in patients 10 to 17 years
of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled
clinical trial in adolescent boys (Tanner Stage II or above) and in girls who were at least oneyear
post-menarche.
In this limited controlled study, there was generally no detectable effect on growth or sexual
maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls.
However, the effects of ezetimibe for a treatment period >33 weeks on growth and sexual
maturation have not been studied (see sections 4.2 and 4.8).
The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40mg
daily have not been studied in pediatric patients 10 to 17 years of age.
Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal
girls (see sections 4.2 and4.8).
The long-term efficacy of therapy with ezetimibe in patients below 17 years of age to reduce
morbidity and mortality in adulthood has not been studied. Fibrates
The safety and efficacy of ezetimibe administered with fibrates have not been established
(see above and sections 4.3and 4.5).
Anticoagulants
If Lunia is added to warfarin, another coumarin anticoagulant, or fluindione, the International
Normalized Ratio (INR) should be appropriately monitored (see section 4.5).
Interstitial lung disease
Cases of interstitial lung disease have been reported with some statins, including
simvastatin, especially with long term therapy (see section 4.8). Presenting features can
include dyspnea, non-productive cough and deterioration in general health (fatigue, weight
loss and fever). If it is suspected a patient has developed interstitial lung disease, Lunia
therapy should be discontinued.
Excipients
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
Lunia contains less than 0.75 sodium per tablet, that is to say essentially sodium-free.

Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase
inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or
transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma
concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further
information about their potential interactions with simvastatin and/or the potential for
enzyme or transporter alterations and possible adjustments to dose and regimens.
Pharmacodynamics interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when given
alone
The risk of myopathy, including rhabdomyolysis, is increased during concomitant
administration of simvastatin with fibrates. Additionally, there is a pharmacokinetic interaction
of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see below
Pharmacokinetic interactions and sections 4.3 and 4.4). Rare cases of
myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipidmodifying
doses (≥ 1 g/day) of niacin (see section 4.4).
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a
preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see section
5.3). Although the relevance of this preclinical finding to humans is unknown, coadministration
of Lunia with fibrates is not recommended (see section 4.4).
Pharmacokinetic interactions
Prescribing recommendations for interacting agents are summarized in the table below
(further details are provided in the text; see also sections 4.2, 4.3, and 4.4). 

Effects of other medicinal products on Lunia
Lunia
Niacin: In a study of 15 healthy adults, concomitant ezetimibe/simvastatin (10/20 mg daily for
7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid 19%) administered as NIASPAN extended-release tablets (1000 mg for2 days and 2000 mg
for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly
increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and
simvastatin acid (35%) (see sections 4.2 and 4.4).
Drug interaction studies with higher doses of simvastatin have not been investigated.
Ezetimibe
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe
but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not
considered clinically significant.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area
under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately
55%. The incremental LDL-C reduction due to adding Lunia to cholestyramine may be
lessened by this interaction (see section 4.2).
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50
mL/min on a stable dose of ciclosporin, a single 10-mg dose of ezetimibe resulted in a 3.4-
fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a
healthy control population, receiving ezetimibe alone, from another study (n = 17). In a
different study, a renal transplant patient with severe renal impairment who was receiving
ciclosporin and multiple other medications demonstrated a 12-fold greater exposure to total
ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period
crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8days
with a single 100-mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in
ciclosporin AUC (range 10%decrease to 51% increase) compared to a single 100-mg dose
of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on
ciclosporin exposure in renal transplant patients has not been conducted. Concomitant
administration of Lunia with ciclosporin is contraindicated (see section 4.3).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe
concentrations approximately1.5- and 1.7-fold, respectively. Although these increases are
not considered clinically significant, co-administration of Lunia with gemfibrozil is
contraindicated and with other fibrates is not recommended (see sections 4.3 and 4.4).
Simvastatin
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450
3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of
HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors
include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir,
nefazodone, and medicinal products containing cobicistat. Concomitant administration of
itraconazole resulted in a more than 10-foldincrease in exposure to simvastatin acid (the
active beta-hydroxy acid metabolite). Telithromycin caused an 11-foldincrease in exposure
to simvastatin acid.
Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease
inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin,
nefazodone, and medicinal products containing cobicistat is contraindicated, as well as
gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with potentCYP3A4     
inhibitors (agents that increase AUC approximately 5-fold or greater) is unavoidable, therapy
with Lunia must be suspended (and use of an alternative statin considered) during the
course of treatment. Caution should be exercised when combining Lunia with certain other
less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.2 and
4.4).
Ticagrelor: Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by
81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with
some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with doses of
simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should
be weighed against potential benefits. There was no effect of simvastatin on ticagrelor
plasma levels. The concomitant use of ticagrelor with doses of simvastatin greater than 40
mg is not recommended.
Fluconazole: Rare cases of rhabdomyolysis associated with concomitant administration of
simvastatin and fluconazole have been reported (see section 4.4).
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant
administration of ciclosporin with Lunia; therefore, use with ciclosporin is contraindicated
(see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has
been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for
simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant
administration of danazol with Lunia; therefore, use with danazol is contraindicated (see
sections 4.3 and 4.4).
Gemfibrozil: Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to
inhibition of the glucuronidation pathway and/or OATP1B1 (see sections 4.3 and 4.4).
Concomitant administration with gemfibrozil is contraindicated.
Fusidic acid: The risk of myopathy, including rhabdomyolysis, may be increased by the
concomitant administration of systemic fusidic acid with statins. The mechanism of this
interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown.
There have been reports of rhabdomyolysis (including some fatalities) inpatients receiving
this combination. Co-administration of this combination may cause increased plasma
concentrations of both agents.
If treatment with systemic fusidic acid is necessary, Lunia treatment should be discontinued
throughout the duration of the fusidic acid treatment. Also see section 4.4.
Amiodarone: The risk of myopathy and rhabdomyolysis is increased by concomitant
administration of amiodarone with simvastatin (see section 4.4). In a clinical trial, myopathy
was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the
dose of Lunia should not exceed 10/20 mg daily in patients receiving concomitant
medication with amiodarone.
Calcium Channel Blockers
• Verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant
administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a
pharmacokinetic study, concomitant administration of simvastatin with verapamil resulted in
2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of  CYP3A4.Therefore, the dose of Lunia should not exceed 10/20 mg daily in patients receiving
concomitant medication with verapamil.
• Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant
administration of diltiazem with simvastatin 80 mg (see section 4.4). In a pharmacokinetic
study, concomitant administration of diltiazem with simvastatin caused a 2.7-fold increase in
exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose
of Lunia should not exceed 10/20 mg daily in patients receiving concomitant medication with
diltiazem.
• Amlodipine: Patients on amlodipine treated concomitantly with simvastatin have an
increased risk of myopathy. In a pharmacokinetic study, concomitant administration of
amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose
of Lunia should not exceed 10/20 mg daily in patients receiving concomitant medication with
amlodipine.
Lomitapide: The risk of myopathy and rhabdomyolysis may be increased by concomitant
administration of lomitapide with simvastatin (see sections 4.3 and 4.4). Therefore, in
patients with HoFH, the dose of Lunia must not exceed 10/40mg daily in patients receiving
concomitant medication with lomitapide.
Moderate Inhibitors of CYP3A4: Patients taking other medicines labelled as having a
moderate inhibitory effect onCYP3A4 concomitantly with Lunia, particularly higher Lunia
doses, may have an increased risk of myopathy (see section 4.4).
Inhibitors of the Transport Protein OATP1B1: Simvastatin acid is a substrate of the transport
protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the
transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid
and an increased risk of myopathy (see sections 4.3 and 4.4).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of
medicinal products that are inhibitors of BCRP, including products containing elbasvir or
grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased
risk of myopathy (see sections 4.2 and 4.4).
Grapefruit juice: Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large
quantities (over 1 liter daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in
exposure to simvastatin acid. Intake of 240 mL of grapefruit juice in the morning and
administration of simvastatin in the evening also resulted in a 1.9-fold increase. Intake of
grapefruit juice during treatment with Lunia should therefore be avoided.
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant
administration of colchicine and simvastatin, in patients with renal impairment. Close clinical
monitoring of such patients taking this combination is advised.
Rifampicin: Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term
rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of
simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma
concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant
administration of rifampicin.
Niacin: Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered
with lipid-modifying doses (≥1 g/day) of niacin (see section 4.4). Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant
administration of HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin)
and daptomycin (see section 4.4).
Effects of Lunia on the pharmacokinetics of other medicinal products
Ezetimibe
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450
drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been
observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2,
2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no
significant effect on bioavailability of warfarin and prothrombin time in a study of twelve
healthy adult males. However, there have been post-marketing reports of increased
International Normalized Ratio (INR) in patients who had ezetimibe added to warfarin or
fluindione. If Lunia is added to warfarin, another coumarin anticoagulant, or fluindione, INR
should be appropriately monitored (see section 4.4).
Simvastatin: Simvastatin does not have an inhibitory effect on cytochrome P450 3A4.
Therefore, simvastatin is not expected to affect plasma concentrations of substances
metabolized via cytochrome P450 3A4.
Oral anticoagulants: In two clinical studies, one in normal volunteers and the other in
hypercholesterolemia patients, simvastatin 20-40 mg/day modestly potentiated the effect of
coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio
(INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient
studies, respectively. Very rare cases of elevated INR have been reported. In patients taking
coumarin anticoagulants, prothrombin time should be determined before starting Lunia and
frequently enough during early therapy to ensure that no significant alteration of prothrombin
time occurs. Once a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on coumarin anticoagulants.
If the dose of Lunia is changed or discontinued, the same procedure should be repeated.
Simvastatin therapy has not been associated with bleeding or with changes in prothrombin
time in patients not taking anticoagulants.
Pediatric population
Interaction studies have only been performed in adults.

Pregnancy
Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs
during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolemia.
Lunia
Lunia is contraindicated during pregnancy. No clinical data are available on the use of Lunia
during pregnancy. Animal studies on combination therapy have demonstrated reproduction
toxicity (see section 5.3). Simvastatin
The safety of simvastatin in pregnant women has not been established. No controlled clinical
trials with simvastatin have been conducted in pregnant women. Rare reports of congenital
anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been
received. However, in an analysis of approximately 200 prospectively followed pregnancies
exposed during the first trimester to simvastatin or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in
the general population. This number of pregnancies was statistically sufficient to exclude a
2.5-fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of
patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs
from that observed in the general population, maternal treatment with simvastatin may
reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For
this reason, Lunia must not be used in women who are pregnant, trying to become pregnant
or suspect they are pregnant. Treatment with Lunia must be suspended for the duration of
pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).
Ezetimibe
No clinical data are available on the use of ezetimibe during pregnancy.
Breast-feeding
Lunia is contraindicated during lactation. Studies on rats have shown that ezetimibe is
excreted into breast milk. It is not known if the active components of Lunia are secreted into
human breast milk (see section 4.3).
Fertility
Ezetimibe
No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe
had no effect on the fertility of male or female rats (see section 5.3).
Simvastatin
No clinical trial data are available on the effects of simvastatin on human fertility. Simvastatin
had no effect on the fertility of rats male and female (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed.
However, when driving vehicles or operating machines, it should be taken into account that
dizziness has been reported.

Lunia (or co-administration of ezetimibe and simvastatin equivalent to Lunia) has been
evaluated for safety in approximately 12,000 patients in clinical trials.
The following adverse reactions were observed in clinical studies of ezetimibe/simvastatin in
patients treated with ezetimibe/simvastatin (n = 2404) and at a greater incidence than
placebo (n = 1340), in patients treated with ezetimibe/simvastatin (n = 9595) and at a greater
incidence than statins administered alone (n = 8883) in clinical studies of ezetimibe or
simvastatin, and/or reported from post-marketing use with ezetimibe/simvastatin or ezetimibe or simvastatin. These reactions are presented in Table 1 by system organ class
and by frequency.
The frequencies of adverse events are ranked according to the following: Very common (≥
1/10), Common (≥ 1/100, <1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, <
1/1000), Very Rare (< 1/10,000) including isolated reports, and Not Known (cannot be
estimated from the available data). 

--------------------------------------------------------

* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80
mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively) (see
sections 4.4 and 4.5).
** There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an
autoimmune myopathy, during or after treatment with some statins. IMNM is clinically
characterized by: persistent proximal muscle weakness and elevated serum creatine kinase,
which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing
myopathy without significant inflammation; improvement with immunosuppressive agents
(see section 4.4).
Pediatric population
In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial
hypercholesterolemia (n =248), elevations of ALT and/or AST (≥ 3X ULN, consecutive) were
observed in 3% (4 patients) of the ezetimibe/simvastatin patients compared to 2% (2
patients) in the simvastatin monotherapy group; these figures were respectively 2% (2
patients) and 0% for elevation of CPK (≥ 10X ULN). No cases of myopathy were reported.
This trial was not suited for comparison of rare adverse drug reactions.
Patients with Coronary Heart Disease and ACS Event History
In the IMPROVE-IT study (see section 5.1), involving 18,144 patients treated with either
ezetimibe/simvastatin 10/40 mg (n = 9067; of whom 6% were up titrated to
ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n = 9077; of whom 27% were up
titrated to simvastatin 80 mg), the safety profiles were similar during a median follow-up
period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for
patients treated with ezetimibe/simvastatin and 10.1% for patients treated with simvastatin.
The incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin,
where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥
10 times ULN or two consecutive observations of CK≥ 5 and < 10 times ULN. The incidence
of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where
rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥ 10
times ULN with evidence of renal injury, ≥ 5times ULN and < 10 times ULN on two
consecutive occasions with evidence of renal injury or CK ≥ 10,000 IU/L without evidence of
renal injury. The incidence of consecutive elevations of transaminases (≥ 3 X ULN) was
2.5% for ezetimibe/simvastatin and 2.3% for simvastatin. (See section 4.4.) Gallbladderrelated
adverse effects were reported in 3.1% vs 3.5% of patients allocated to
ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy
hospitalizations was 1.5% in both treatment groups. Cancer (defined as any new
malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.
Patients with Chronic Kidney Disease
In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9000
patients treated with ezetimibe/simvastatin 10/20 mg daily (n = 4650) or placebo (n = 4620),
the safety profiles were comparable during a median follow-up period of4.9 years. In this
trial, only serious adverse events and discontinuations due to any adverse events were
recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients
treated with ezetimibe/simvastatin, 9.8% in patients treated with placebo). The incidence of
myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe/simvastatin and 0.1%
in patients treated with placebo. Consecutive elevations of transaminases (> 3 X ULN)
occurred in 0.7% of patients treated with ezetimibe/simvastatin compared with 0.6% of patients treated with placebo (see section 4.4). In this trial, there were no statistically
significant increases in the incidence of pre-specified adverse events, including cancer
(9.4% for ezetimibe/simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or
complications of gallstones or pancreatitis.
Laboratory Values
In co-administration trials, the incidence of clinically important elevations in serum
transaminases (ALT and/or AST ≥ 3 XULN, consecutive) was 1.7% for patients treated with
ezetimibe/simvastatin. These elevations were generally asymptomatic, not associated with
cholestasis, and returned to baseline after discontinuation of therapy or with continued
treatment (see section 4.4)
Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.2% of the patients treated
with ezetimibe/simvastatin.
Post-marketing Experience
An apparent hypersensitivity syndrome has been reported rarely which has included some of
the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica,
dermatomyositis, vasculitis, thrombocytopaenia, eosinophilia, red blood cell sedimentation
rate increased, arthritis and arthralgia, urticaria, photosensitivity reaction, pyrexia, flushing,
dyspnea and malaise.
Increases in HbA1c and fasting serum glucose levels have been reported with statins,
including simvastatin.
There have been rare post-marketing reports of cognitive impairment (e.g. memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including
simvastatin. The reports are generally nonserious, and reversible upon statin
discontinuation, with variable times to symptom onset (1 day to years) and symptom
resolution (median of 3 weeks).
The following additional adverse events have been reported with some statins:
• Sleep disturbances, including nightmares
• Sexual dysfunction
• Diabetes mellitus: Frequency will depend on the presence or absence of risk factors
(fasting blood glucose ≥ 5.6mmol/L, BMI > 30 kg/m2, raised triglycerides, history of
hypertension).
To report any side effect(s):
 Saudi Arabia:
− The National Pharmacovigilance Centre (NPC)
o Fax: +966-11-205-7662
o SFDA Call Center: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: https://ade.sfda.gov.sa
 Other GCC States:
Please contact the relevant competent authority.

 

Lunia
In the event of an overdose, symptomatic and supportive measures should be employed.
Co-administration of ezetimibe (1000 mg/kg) and simvastatin (1000 mg/kg) was welltolerated
in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were
observed in these animals. The estimated oral LD50 for both species was ezetimibe ≥
1000mg/kg/simvastatin ≥ 1000 mg/kg.
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14
days, or 40 mg/day to 18patients with primary hypercholesterolemia for up to 56 days, was
generally well tolerated. A few cases of over dosage have been reported; most have not
been associated with adverse experiences. Reported adverse experiences have not been
serious. In animals, no toxicity was observed after single oral doses of 5000 mg/kg of
ezetimibe in rats and mice and 3000 mg/kg in dogs.
Simvastatin
A few cases of over dosage have been reported; the maximum dose taken was 3.6 g. All
patients recovered without sequelae.

Pharmacotherapeutic group: HMG-CoA reductase inhibitors in combination with other lipid
modifying agents, ATC code: C10BA02
Lunia(ezetimibe/simvastatin) is a lipid-lowering product that selectively inhibits the intestinal
absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of
cholesterol.
Mechanism of action
Lunia
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Lunia
contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary
mechanisms of action. ezetimibe/simvastatin reduces elevated total cholesterol (total-C),
LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein
cholesterol(non-HDL-C), and increases high-density lipoprotein cholesterol (HDL-C) through
dual inhibition of cholesterol absorption and synthesis.
Ezetimibe
Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a
mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g.
statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The
molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1(NPC1L1),
which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of
cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins
reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical study in 18hypercholesterolaemic
patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with
placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for
inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with
no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl
estradiol, or fat soluble vitamins A and D.
Simvastatin
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the
corresponding active β-hydroxy acid form which has a potent activity in inhibiting HMG-CoA
reductase (3 hydroxy - 3 methyl glutaryl CoA reductase). This enzyme catalysis the
conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of
cholesterol.
Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations.
LDL is formed from very-low-density protein (VLDL) and is catabolized predominantly by the
high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may
involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL
receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein
B also falls substantially during treatment with simvastatin. In addition, simvastatin
moderately increases HDL-C and reduces plasma TG. As a result of these changes, the
ratios of total- to HDL-C and LDL- to HDL-C are reduced.
Clinical efficacy and safety
In controlled clinical studies, ezetimibe/simvastatin significantly reduced total-C, LDL-C, Apo
B, TG, and non-HDL-C, and increased HDL-C in patients with hypercholesterolemia.
Prevention of Cardiovascular Events
ezetimibe/simvastatin has been shown to reduce major cardiovascular events in patients
with coronary heart disease and ACS event history.
The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)
was a multicenter, randomized, double-blind, active-control study of 18,144 patients enrolled
within 10 days of hospitalization for acute coronary syndrome (ACS; either acute myocardial
infarction [MI] or unstable angina [UA]). Patients had an LDL-C ≤ 125 mg/dL (≤3.2 mmol/L)
at the time of presentation with ACS if they had not been taking lipid-lowering therapy, or ≤
100 mg/dL (≤ 2.6mmol/L) if they had been receiving lipid-lowering therapy. All patients were
randomized in a 1:1 ratio to receive either ezetimibe/simvastatin 10/40 mg (n = 9067) or
simvastatin 40 mg (n = 9077) and followed for a median of 6.0 years.
Patients had a mean age of 63.6 years; 76% were male, 84% were Caucasian, and 27%
were diabetic. The average LDL-C value at the time of study qualifying event was 80 mg/dL
(2.1 mmol/L) for those on lipid-lowering therapy (n =6390) and 101 mg/dL (2.6 mmol/L) for
those not on previous lipid-lowering therapy (n = 11594). Prior to the hospitalization for the
qualifying ACS event, 34% of the patients were on statin therapy. At one year, the average
LDL-C for patients continuing on therapy was 53.2 mg/dL (1.4 mmol/L) for the
ezetimibe/simvastatin group and 69.9 mg/dL (1.8 mmol/L) for the simvastatin monotherapy
group. Lipid values were generally obtained for patients who remained on study therapy.    
The primary endpoint was a composite consisting of cardiovascular death, major coronary
events (MCE; defined as non-fatal myocardial infarction, documented unstable angina that 

required hospitalization, or any coronary revascularization procedure occurring at least 30
days after randomized treatment assignment) and non-fatal stroke. The study demonstrated
that treatment with ezetimibe/simvastatin provided incremental benefit in reducing the
primary composite endpoint of cardiovascular death, MCE, and non-fatal stroke compared
with simvastatin alone (relative risk reduction of 6.4%, p =0.016). The primary endpoint
occurred in 2572 of 9067 patients (7-year Kaplan-Meier [KM] rate 32.72%) in the
ezetimibe/simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the
simvastatin alone group. (See Figure 1 and Table 2.) Total mortality was unchanged in this
high risk group (see Table 2).
There was an overall benefit for all strokes; however, there was a small non-significant
increase in hemorrhagic stroke in the ezetimibe-simvastatin group compared with
simvastatin alone (see Table 2). The risk of hemorrhagic stroke for ezetimibe coadministered
with higher potency statins in long-term outcome studies has not been
evaluated.
The treatment effect of ezetimibe/simvastatin was generally consistent with the overall
results across many sub groups, including sex, age, race, medical history of diabetes
mellitus, baseline lipid levels, prior statin therapy, prior stroke, and hypertension.
Figure 1: Effect of ezetimibe/simvastatin on the Primary Composite Endpoint of
Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke
Table 2 Major Cardiovascular Events by Treatment Group in All Randomized Patients
in IMPROVE-IT

Primary Hypercholesterolemia
In a double-blind, placebo-controlled, 8-week study, 240 patients with hypercholesterolemia
already receiving simvastatin monotherapy and not at National Cholesterol Education
Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/L [100 to 160 mg/dL], depending on baseline
characteristics) were randomized to receive either ezetimibe 10 mg or placebo in addition to
their on-going simvastatin therapy. Among simvastatin-treated patients not at LDL-C goal at
baseline (~80%), significantly more patients randomized to ezetimibe co-administered with
simvastatin achieved their LDL-C goal at study endpoint compared to patients randomized to
placebo co-administered with simvastatin, 76% and21.5%, respectively.
The corresponding LDL-C reductions for ezetimibe or placebo co-administered with
simvastatin were also significantly different (27% or 3%, respectively). In addition, ezetimibe

co-administered with simvastatin significantly decreased total-C, Apo B, and TG compared
with placebo co-administered with simvastatin.
In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus
treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and
simvastatin 20 mg for a minimum of 6 weeks with a mean LDL-C of 2.4 mmol/L (93 mg/dL),
were randomized to receive either simvastatin 40 mg or the co-administered active
ingredients equivalent to ezetimibe/simvastatin 10 mg/20 mg. ezetimibe/simvastatin 10
mg/20 mg was significantly more effective than doubling the dose of simvastatin to 40 mg in
further reducing LDL-C (-21% and 0%, respectively), total-C (-14% and -1%,respectively),
Apo B (-14% and -2%, respectively), and non-HDL-C (-20% and -2%, respectively) beyond
the reductions observed with simvastatin 20 mg. Results for HDL-C and TG between the two
treatment groups were not significantly different. Results were not affected by type of
thiazolidinedione treatment.
The efficacy of the different dose-strengths of ezetimibe/simvastatin (10/10 to 10/80 mg/day)
was demonstrated in a multicenter, double-blind, placebo-controlled 12-week trial that
included all available doses of ezetimibe/simvastatin and all relevant doses of simvastatin.
When patients receiving all doses of ezetimibe/simvastatin were compared to those
receiving all doses of simvastatin, ezetimibe/simvastatin significantly lowered total-C, LDL-C,
and TG (see Table 3) as well as Apo B (-42% and -29%, respectively), non-HDL-C (-49%
and -34%, respectively) and C-reactive protein (-33% and -9%, respectively). The effects of
ezetimibe/simvastatin on HDL-C were similar to the effects seen with simvastatin. Further
analysis showed ezetimibe/simvastatin significantly increased HDL-C compared with
placebo.
Table 3 Response to ezetimibe/simvastatin in Patients with Primary
Hypercholesterolemia (Meana % Change from Untreated Baselineb)

In a similarly designed study, results for all lipid parameters were generally consistent. In a
pooled analysis of these two studies, the lipid response to ezetimibe/simvastatin was similar
in patients with TG levels greater than or less than 200 mg/dL.
In a multicenter, double-blind, controlled clinical study (ENHANCE), 720 patients with
heterozygous familial hypercholesterolemia were randomized to receive ezetimibe 10 mg in
combination with simvastatin 80 mg (n = 357) or simvastatin 80 mg (n = 363) for 2 years.
The primary objective of the study was to investigate the effect of the ezetimibe/simvastatin
combination therapy on carotid artery intima-media thickness (IMT) compared to simvastatin
monotherapy. The impact of this surrogate marker on cardiovascular morbidity and mortality
is still not demonstrated.
The primary endpoint, the change in the mean IMT of all six carotid segments, did not differ
significantly (p = 0.29) between the two treatment groups as measured by B-mode
ultrasound. With ezetimibe 10 mg in combination with simvastatin 80 mg or simvastatin 80
mg alone, intima-medial thickening increased by 0.0111 mm and 0.0058 mm, respectively,
over the study's 2 year duration (baseline mean carotid IMT 0.68 mm and 0.69 mm
respectively).
Ezetimibe 10 mg in combination with simvastatin 80 mg lowered LDL-C, total-C, Apo B, and
TG significantly more than simvastatin 80 mg. The percent increase in HDL-C was similar for
the two treatment groups. The adverse reactions reported for ezetimibe 10 mg in
combination with simvastatin 80 mg were consistent with its known safety profile.
In two large placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study
(20-40 mg; n = 4,444 patients) and the Heart Protection Study (40 mg; n = 20,536 patients),
the effects of treatment with simvastatin were assessed in patients at high risk of coronary
events because of existing coronary heart disease, diabetes, peripheral vessel disease,
history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and
stroke; and the need for coronary and non-coronary revascularization procedures.
The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
(SEARCH) evaluated the effect of treatment with simvastatin 80 mg versus 20 mg (median
follow-up 6.7 years) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI,
coronary revascularization procedure, non-fatal or fatal stroke, or peripheral
revascularization procedure) in 12,064 patients with a history of myocardial infarction. There
was no significant difference in the incidence of MVEs between the 2 groups; simvastatin 20
mg (n = 1553; 25.7%) vs. simvastatin 80 mg (n = 1477;24.5%); RR 0.94, 95% CI: 0.88 to
1.01. The absolute difference in LDL-C between the two groups over the course of the study
was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups
except that the incidence of myopathy was approximately 1.0% for patients on simvastatin
80 mg compared with 0.02% for patients on20 mg. Approximately half of these myopathy
cases occurred during the first year of treatment. The incidence of myopathy during each
subsequent year of treatment was approximately 0.1%.
Pediatric population
In a multicenter, double-blind, controlled study, 142 boys (Tanner Stage II and above) and
106 post-menarchal girls, 10to 17 years of age (mean age 14.2 years) with heterozygous
familial hypercholesterolemia (HeFH) with baseline LDL-C levels between 4.1 and 10.4
mmol/L were randomized to either ezetimibe 10 mg co-administered with simvastatin (10, 20
or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, co-administered ezetimibe and
40 mg simvastatin or 40mg simvastatin alone for the next 27 weeks, and open-label coadministered
ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
At Week 6, ezetimibe co-administered with simvastatin (all doses) significantly reduced total-
C (38% vs 26%), LDL-C(49% vs 34%), Apo B (39% vs 27%), and non-HDL-C (47% vs 33%)
compared to simvastatin (all doses) alone. Results for the two treatment groups were similar
for TG and HDL-C (-17% vs -12% and +7% vs +6%, respectively). At Week 33, results were
consistent with those at Week 6 and significantly more patients receiving ezetimibe and 40
mg simvastatin (62%) attained the NCEP AAP ideal goal (< 2.8 mmol/L [110 mg/dL]) for
LDL-C compared to those receiving 40 mg simvastatin (25%). At Week 53, the end of the
open label extension, the effects on lipid parameters were maintained.
The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40 mg
daily have not been studied in pediatric patients 10 to 17 years of age. The long-term
efficacy of therapy with ezetimibe in patients below 17 years of age to reduce morbidity and
mortality in adulthood has not been studied.
The European Medicines Agency has waived the obligation to submit the results of studies
with ezetimibe/simvastatin in all subsets of the pediatric population in hypercholesterolemia
(see section 4.2 for information on pediatric use). Homozygous Familial Hypercholesterolemia (HoFH)
A double-blind, randomized, 12-week study was performed in patients with a clinical and/or
genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n = 14)
receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg
(n = 5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered
ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10 mg/40 mg
and 10 mg/80 mg pooled, n = 9), produced a reduction of LDL-C of 23% from baseline on
simvastatin 40 mg. In those patients co-administered ezetimibe and simvastatin equivalent
to ezetimibe/simvastatin (10 mg/80 mg, n = 5), a reduction of LDL-C of 29% from baseline
on simvastatin 40mg was produced.
Prevention of Major Vascular Events in Chronic Kidney Disease (CKD)
The Study of Heart and Renal Protection (SHARP) was a multi-national, randomized,
placebo-controlled, double-blind study conducted in 9438 patients with chronic kidney
disease, a third of whom were on dialysis at baseline. A total of4650 patients were allocated
to ezetimibe/simvastatin 10/20 and 4620 to placebo, and followed for a median of 4.9 years.
Patients had a mean age of 62 and 63% were male, 72% Caucasian, 23% diabetic and, for
those not on dialysis, the mean estimated glomerular filtration rate (eGFR) was 26.5
mL/min/1.73 m2. There were no lipid entry criteria. Mean LDL-C at baseline was 108 mg/dL.
After one year, including patients no longer taking study medication, LDL-C was reduced
26% relative to placebo by simvastatin 20 mg alone and 38% by ezetimibe/simvastatin 10/20
mg.
The SHARP protocol-specified primary comparison was an intention-to-treat analysis of
"major vascular events" (MVE; defined as non-fatal MI or cardiac death, stroke, or any
revascularization procedure) in only those patients initially randomized to the
ezetimibe/simvastatin (n = 4193) or placebo (n = 4191) groups. Secondary analyses
included the same composite analyzed for the full cohort randomized (at study baseline or at
year 1) to ezetimibe/simvastatin (n = 4650) or placebo (n = 4620) as well as the components
of this composite.
The primary endpoint analysis showed that ezetimibe/simvastatin significantly reduced the
risk of major vascular events (749 patients with events in the placebo group vs 639 in the
ezetimibe/simvastatin group) with a relative risk reduction of 16% (p = 0.001).
Nevertheless, this study design did not allow for a separate contribution of the
monocomponent ezetimibe to efficacy to significantly reduce the risk of major vascular
events in patients with CKD.
The individual components of MVE in all randomized patients are presented in Table 4.
ezetimibe/simvastatin significantly reduced the risk of stroke and any revascularization, with
non-significant numerical differences favoring ezetimibe/simvastatin for non-fatal MI and
cardiac death.

   Table 4 Major Vascular Events by Treatment Group in all randomized patients in
SHARPa

The absolute reduction in LDL cholesterol achieved with ezetimibe/simvastatin was lower
among patients with a lower baseline LDL-C(<2.5 mmol/L) and patients on dialysis at
baseline than the other patients, and the corresponding risk reductions in these two groups
were attenuated.
Aortic Stenosis
The Simvastatin and Ezetimibe for the Treatment of Aortic Stenosis (SEAS) study was a
multicenter, double-blind, placebo-controlled study with a median duration of 4.4 years
conducted in 1873 patients with asymptomatic aortic stenosis (AS), documented by Dopplermeasured
aortic peak flow velocity within the range of 2.5 to 4.0 m/s. Only patients who were
considered not to require statin treatment for purposes of reducing atherosclerotic
cardiovascular disease risk were enrolled. Patients were randomized 1:1 to receive placebo
or co-administered ezetimibe 10 mg and simvastatin 40 mg daily.
The primary endpoint was the composite of major cardiovascular events (MCE) consisting of
cardiovascular death, aortic valve replacement (AVR) surgery, congestive heart failure (CHF) as a result of progression of AS, non-fatal myocardial infarction, coronary artery
bypass grafting (CABG), percutaneous coronary intervention (PCI), hospitalizations for
unstable angina, and non-hemorrhagic stroke. The key secondary endpoints were
composites of subsets of the primary endpoint event categories.
Compared to placebo, ezetimibe/simvastatin 10/40 mg did not significantly reduce the risk of
MCE.
The primary outcome occurred in 333 patients (35.3%) in the ezetimibe / simvastatin group
and in 355 patients (38.2%)in the placebo group (hazard ratio in the ezetimibe / simvastatin
group, 0.96; 95% confidence interval, 0.83 to 1.12; p =0.59). Aortic valve replacement was
performed in 267 patients (28.3%) in the ezetimibe / simvastatin group and in 278patients
(29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; p = 0.97). Fewer
patients had ischemic cardiovascular events in the ezetimibe / simvastatin group (n = 148)
than in the placebo group (n = 187) (hazard ratio,0.78; 95% CI, 0.63 to 0.97; p = 0.02),
mainly because of the smaller number of patients who underwent coronary artery bypass
grafting.
Cancer occurred more frequently in the ezetimibe / simvastatin group (105 versus 70, p =
0.01). The clinical relevance of this observation is uncertain as in the bigger SHARP trial the
total number of patients with any incident cancer (438 in the ezetimibe/ simvastatin versus
439 placebo group) did not differ. In addition, in the IMPROVE-IT trial the total number of
patients with any new malignancy (853 in the ezetimibe/simvastatin group versus 863 in the
simvastatin group) did not differ significantly and therefore the finding of SEAS trial could not
be confirmed by SHARP or IMPROVE-IT.

No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered
with simvastatin.
Absorption
Lunia
Lunia is bioequivalent to co-administered ezetimibe and simvastatin.
Ezetimibe
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a
pharmacologically active ephenolic glucuronide (ezetimibe-glucuronide). Mean maximum
plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to
12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as
the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high-fat or non-fat meals) had no effect on the oral
bioavailability of ezetimibe when administered as 10-mg tablets.
Simvastatin The availability of the active β-hydroxy acid to the systemic circulation following an oral dose
of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic
first-pass extraction. The major metabolites of simvastatin present in human plasma are the
β-hydroxy acid and four additional active metabolites.
Relative to the fasting state, the plasma profiles of both active and total inhibitors were not
affected when simvastatin was administered immediately before a test meal.
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma
proteins, respectively.
Simvastatin
Both simvastatin and the β-hydroxyacid are bound to human plasma proteins (95%).
The pharmacokinetics of single and multiple doses of simvastatin showed that no
accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic
studies, the maximum plasma concentration of inhibitors occurred1.3 to 2.4 hours post-dose.
Biotransformation
Ezetimibe
Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation
(a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a
phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibeglucuronide
are the major drug-derived compounds detected in plasma, constituting
approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both
ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of
significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is
approximately 22 hours.
Simvastatin
Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-
hydroxy acid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the
liver; the rate of hydrolysis in human plasma is very slow.
In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction.
The extraction in the liver is dependent on the hepatic blood flow. The liver is its primary site
of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability
of active drug to the systemic circulation is low.
Following an intravenous injection of the β-hydroxy acid metabolite, its half-life averaged 1.9
hours.
Elimination
Ezetimibe
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe
accounted for approximately93% of the total radioactivity in plasma. Approximately 78% and
11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of
radioactivity in the plasma.
Simvastatin
Simvastatin acid is taken up actively into the hepatocytes by the transporter OATP1B1.
Simvastatin is a substrate of the efflux transporter BCRP.
Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was
excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the
faeces represents absorbed drug equivalents excreted in bile as well as unabsorbed drug.
Following an intravenous injection of the β-hydroxyacid metabolite, an average of only
0.3%of the IV dose was excreted in urine as inhibitors.
Special Populations
Pediatric Population
The absorption and metabolism of ezetimibe are similar between children and adolescents
(10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic
differences between adolescents and adults. Pharmacokinetic data in the pediatric
population < 10 years of age are not available. Clinical experience in pediatric and
adolescent patients includes patients with HoFH, HeFH, or sitosterolaemia (see section 4.2).
Elderly
Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥ 65 years)
than in the young (18 to 45years). LDL-C reduction and safety profile are comparable
between elderly and younger subjects treated with ezetimibe (see section 4.2).
Hepatic impairment
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased
approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 or 6),
compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with
moderate hepatic impairment (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe
was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No
dosage adjustment is necessary for patients with mild hepatic impairment. Due to the
unknown effects of the increased exposure to ezetimibe in patients with moderate or severe
(Child-Pugh score > 9) hepatic impairment, ezetimibe is not recommended in these patients
(see sections 4.2 and 4.4).
Renal impairment
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n = 8; mean
CrCl ≤ 30 mL/min), the mean AUC for total ezetimibe was increased approximately 1.5-fold,
compared to healthy subjects (n = 9) (see section 4.2).
An additional patient in this study (post-renal transplant and receiving multiple medications,
including ciclosporin) had a12-fold greater exposure to total ezetimibe.
Simvastatin
In a study of patients with severe renal impairment (creatinine clearance < 30 mL/min), the
plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase
inhibitor were approximately two-fold higher than those in healthy volunteers.

   Gender
Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women
than in men. LDL-C reduction and safety profile are comparable between men and women
treated with ezetimibe.
SLCO1B1 polymorphism
Carriers of the SLCO1B1 gene c.521T > C allele have lower OATP1B1 activity. The mean
exposure (AUC) of the main active metabolite, simvastatin acid is 120% in heterozygote
carriers (CT) of the C allele and 221% in homozygote (CC)carriers relative to that of patients
who have the most common genotype (TT). The C allele has a frequency of 18% in the
European population. In patients with SLCO1B1 polymorphism there is a risk of increased
exposure of simvastatin acid, which may lead to an increased risk of rhabdomyolysis (see
section 4.4).

In co-administration studies with ezetimibe and simvastatin, the toxic effects observed were
essentially those typically associated with statins. Some of the toxic effects were more
pronounced than observed during treatment with statins alone. This is attributed to
pharmacokinetic and/or pharmacodynamics interactions following co-administration. No such
interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure
to doses that were several times higher than the human therapeutic dose (approximately 20
times the AUC level for simvastatin and 1800 times the AUC level for the active metabolite).
There was no evidence that co-administration of ezetimibe affected the myotoxic potential of
simvastatin.
In dogs co-administered ezetimibe and statins, some liver effects were observed at low
exposures (<1 times human AUC). Marked increases in liver enzymes (ALT, AST) in the
absence of tissue necrosis were seen. Histopathologic liver findings (bile duct hyperplasia,
pigment accumulation, mononuclear cell infiltration and small hepatocytes) were observed in
dogs co-administered ezetimibe and simvastatin. These changes did not progress with
longer duration of dosing up to 14 months. General recovery of the liver findings was
observed upon discontinuation of dosing. These findings were consistent with those
described with HMG-CoA inhibitors or attributed to the very low cholesterol levels achieved
in the affected dogs.
The co-administration of ezetimibe and simvastatin was not teratogenic in rats. In pregnant
rabbits a small number of skeletal deformities (fused caudal vertebrae, reduced number of
caudal vertebrae) were observed.
In a series of in vivo and in vitro assays, ezetimibe, given alone or co-administered with
simvastatin, exhibited no genotoxic potential.
Ezetimibe
Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic
effects. In dogs treated for four weeks with ezetimibe (≥ 0.03 mg/kg/day) the cholesterol
concentration in the cystic bile was increased by a factor of 2.5to 3.5. However, in a oneyear
study on dogs given doses of up to 300 mg/kg/day no increased incidence of
cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of ezetimibe
cannot be ruled out.
Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be
teratogenic in rats or rabbits, nor did it affect prenatal or post-natal development. Ezetimibe
crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1000
mg/kg/day.
Simvastatin
Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity,
genotoxicity and carcinogenicity, there are no other risks for the patient than may be
expected on account of the pharmacological mechanism. At maximally tolerated doses in
both the rat and the rabbit, simvastatin produced no fetal malformations, and had no effects
on fertility, reproductive function or neonatal development.

Lactose monohydrate
Citric acid monohydrate
Butylated hydroxyanisole
Propyl gallate
Croscarmellose sodium
Hypromellose
Sodium lauryl sulphate
Ethyl alcohol
Purified water
Magnesium stearate 

Not applicable.

2 years (24 Months).

Store below 30 ºC
Store in the original package in order to protect from moisture and light

Lunia 10 mg ezetimibe /40 mg simvastatin: White to off white, oblong, biconvex tablets
debossed JS35 on one side and plain on another side

Any unused medicinal product or waste material should be disposed of in accordance with
local requirements, Keep out of the reach & sight of children